Renin inhibitors based on the octapeptide sequence, His-Pro-Phe-His-Leu-Leu-Val-Tyr, found between positions six and thirteen of natural substrate, have been developed in this laboratory. Soluble analogs of this sequence, specific for human renin, act as competitive inhibitors and suppress angiotensin I formation. The first objective of the proposed research is to make more effective inhibitors by increasing binding to renin, solubility in vehicles used for in vivo administration, and resistance to catabolic processes. The second objective is to synthesize affinity labels specific for renin. These irreversible inhibitors will covalently bond to functional groups in the active site. Proteolytic digestion of the enzyme-inhibitor complex will produce peptides which can be isolated by affinity chromatography on columns specific for some component of the affinity label. Comparison of the amino acid sequence of these peptides with known sequences from carboxyl-proteases, will establish homology and give insight into the mechanism by which renin acts. These irreversible inhibitors will also be tested in vivo. Pepstatin inhibits a wide variety of carboxyl-proteases. The third objective of this research is to modify pepstatin to increase its specificity for renin. Both inclusion of the statyl-residue into the sequence of the substrate analog renin inhibitors and modification of the active fragment Val-Sta-Ala-Sta, will be tried.